Adjuvant Selpercatinib in Early-Stage RET Fusion-Positive NSCLC

Key Takeaways

• In stage II or IIIA disease, 2-year investigator-assessed event-free survival was higher with selpercatinib than with placebo.
• Across the broader stage IB, II, or IIIA population, event-free survival also favored selpercatinib over placebo.
• Treatment continued for up to 3 years; transaminase elevations were the main adverse events, and three deaths from disease progression occurred in the placebo group.

In a phase 3 NEJM trial, adjuvant selpercatinib was associated with a lower risk of recurrence, progression, or death than placebo after definitive therapy for RET fusion–positive NSCLC, with a hazard ratio of 0.17 in the primary stage II or IIIA population. The double-blind comparison evaluated adjuvant treatment after curative-intent therapy rather than treatment in advanced disease.

The LIBRETTO-432 trial enrolled patients with RET fusion–positive NSCLC after definitive therapy with curative intent, which could include surgery or radiotherapy, with adjuvant systemic anticancer therapy if applicable. Investigators randomly assigned 151 patients to selpercatinib or placebo, with 75 and 76 patients in each group, for up to 3 years. The primary end point was investigator-assessed event-free survival in stage II or IIIA disease; secondary end points included broader event-free survival analyses, blinded independent central review, overall survival, and safety. Median follow-up was 24 months with selpercatinib and 27 months with placebo.

Among 109 patients with stage II or IIIA disease, 2-year investigator-assessed event-free survival was 92% with selpercatinib and 61% with placebo. The hazard ratio for disease recurrence, progression, or death was 0.17, with a 95% confidence interval from 0.06 to 0.51 and a P value below 0.001. Blinded independent central review was consistent with the investigator assessment.

In the full stage IB, II, or IIIA population of 151 patients, 2-year investigator-assessed event-free survival was 94% with selpercatinib and 70% with placebo. The hazard ratio for disease recurrence, progression, or death was 0.17, with a 95% confidence interval from 0.06 to 0.49 and a P value below 0.001. Selpercatinib is a highly selective, potent, CNS-penetrant RET inhibitor approved for RET fusion–positive advanced or metastatic NSCLC.

The most common adverse events during treatment were increased alanine aminotransferase and aspartate aminotransferase levels. In the selpercatinib group, grade 3 or higher alanine aminotransferase elevation occurred in 17% of patients, and grade 3 or higher aspartate aminotransferase elevation occurred in 19%. Three deaths occurred, all in the placebo group, owing to disease progression.

In the Lilly-funded LIBRETTO-432 trial, event-free survival was significantly longer with adjuvant selpercatinib than with placebo in stage II or IIIA RET fusion–positive NSCLC.